Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus

Abstract

Recent evidence suggests that systemic autoimmunity and immunodeficiency are not separate entities, but rather are interconnected processes. Immunodeficiency results from distinct defects of the immune response and primarily presents as infections but also frequently with autoimmune features. Systemic autoimmunity is the combined effect of multiple genetic variations and infectious and immunoregulatory factors that result in dominant autoimmune manifestations, in addition to frequent and opportunistic infections. The overlap in disease manifestations and symptoms suggests that immunodeficiency should be considered in the presence of autoimmunity, and vice versa. In this review, we present the shared or similar aspects of immunodeficiency and autoimmunity using systemic lupus erythematosus as a paradigm and discuss the implications for clinical care.

Fig. 1. Immune system defects and autoimmunity

The development of multiple subclinical infections may represent the triggering event in autoimmune patients that leads to uncontrolled immune system activation and chronic inflammation. A decline in immunity triggered by environmental factors (e.g. diet or psychological effectors) in combination with the presence of mild immune system defects may allow for these infections to develop.

Fig. 2. Scale of severity of immune system-related genetic defects

Milder genetic defects may result in the culmination of multiple subclinical infections and the development of an autoimmunity-based phenotype. More severe genetic defects may manifest by the presence of frequent and/or severe infections and a more immunodeficiency-oriented phenotype.

Fig. I. Type I interferon production

Toll-like receptors (TLRs) in endosomal compartments and cytosolic nucleic acid receptors (CNARs) scan phagocytosed material for the presence of viral particles. Upon recognition of their respective ligands, type I interferons responsible for activating intracellular pathways that promote pathogen clearance are produced (IFNα and IFNβ).